J Clin Pathol: Mol Pathol 2001;54:311–316
Insulin-like growth factor 1 (IGF-1): a growth
hormone
Z Laron
Abstract
Aim—To contribute to the debate about
whether growth hormone (GH) and
insulin-like growth factor 1 (IGF-1) act
independently on the growth process.
Methods—To describe growth in human
and animal models of isolated IGF-1 defi-
ciency (IGHD), such as in Laron syn-
drome (LS; primary IGF-1 deficiency and
GH resistance) and IGF-1 gene or GH
receptor gene knockout (KO) mice.
Results—Since the description of LS in
1966, 51 patients were followed, many
since infancy. Newborns with LS are
shorter (42–47 cm) than healthy babies
(49–52 cm), suggesting that IGF-1 has
some influence on intrauterine growth.
Newborn mice with IGF-1 gene KO are
30% smaller. The postnatal growth rate of
patients with LS is very slow, the distance
from the lowest normal centile increasing
progressively. If untreated, the final height
Endocrinology and is 100–136 cm for female and 109–138 cm
Diabetes Research for male patients. They have acromicia,
Unit, WHO organomicria including the brain, heart,
Collaborating Center
gonads, genitalia, and retardation of skel-
for the Study of
Diabetes in Youth, etal maturation. The availability of bio-
Schneider Children’s synthetic IGF-1 since 1988 has enabled it
Medical Center, Tel to be administered to children with LS. It
Aviv University, 14 accelerated linear growth rates to 8–9 cm
Kaplan Street, Petah in the first year of treatment, compared
Tikva 49202, Tel Aviv,
Israel
with 10–12 cm/year during GH treatment
Z Laron of IGHD. The growth rate in following
years was 5–6.5 cm/year.
Correspondence to: Conclusion—IGF-1 is an important
Professor Laron
laronz@clalit.org.il
growth hormone, mediating the protein
anabolic and linear growth promoting
Accepted 24 April 2001 eVect of pituitary GH. It has a GH
(CNS)
Neurotransmitters
+ (hypothalamus) +
– –
+ –
GHRH GH-S Somatostatin
(pituitary)
+ –
GH
+ –
GHBP
– +
+ +
+ The IGFs are members of a family of insulin
(liver) – –
IGF-1
– several peptides isolated from lower inverte-
+
IGFBP-3; IGFBP-2; IGFBP-1
Target tissues
Figure 1 The cascade of the growth hormone axis. CNS, central nervous system; GH,
growth hormone; GHBP, GH binding protein; GH-S, GH secretagogues; IGF-1,
insulin-like growth factor 1; IGFBPs, IGF binding proteins; +, stimulation; –, inhibition.
www.molpath.com
311
independent growth stimulating eVect,
which with respect to cartilage cells is
possibly optimised by the synergistic ac-
tion with GH.
(J Clin Pathol: Mol Pathol 2001;54:311–316)
Keywords: insulin-like growth factor I; growth hor-
mones; Laron syndrome; growth
In recent years, new technologies have enabled
many advances in the so called growth
hormone (GH) axis (fig 1). Thus, it has been
found that GH secretion from the anterior
pituitary is regulated not only by GH releasing
hormone (GHRH) and somatostatin (GH
secretion inhibiting hormone),1 but also by
other hypothalamic peptides called GH secre-
tagogues,2 which seem to act in synergism with
GHRH3 by inhibiting somatostatin.4 One of
these has been cloned and named Ghrelin.5
The interplay between GHRH and somatosta-
tin induces a pulsatile GH secretion,6 which is
highest during puberty. GH induces the
generation of insulin-like growth factor 1
(IGF-1, also called somatomedin 1) in the liver
and regulates the paracrine production of
IGF-1 in many other tissues.7
IGF-1
IGF-1 and IGF-2 were identified in 1957 by
Salmon and Daughaday8 and designated “sul-
phation factor” by their ability to stimulate
35
-sulphate incorporation into rat cartilage.
Froesch et al described the non-suppressible
insulin-like activity (NSILA) of two soluble
serum components (NSILA I and II).9 In
1972, the labels sulphation factor and NSILA
were replaced by the term “somatomedin”,
denoting a substance under control and medi-
ating the eVects of GH.10 In 1976, Rinderk-
necht and Humbel11 isolated two active sub-
stances from human serum, which owing to
their structural resemblance to proinsulin were
renamed “insulin-like growth factor 1 and 2”
– Sex (IGF-1 and 2). IGF-1 is the mediator of the
steroids anabolic and mitogenic activity of GH.12
(pancreas)
CHEMICAL STRUCTURE
Insulin
related peptides that include relaxin and
brates.13 IGF-1 is a small peptide consisting of
70 amino acids with a molecular weight of
7649 Da.14 Similar to insulin, IGF-1 has an A
and B chain connected by disulphide bonds.
The C peptide region has 12 amino acids. The
structural similarity to insulin explains the
ability of IGF-1 to bind (with low aYnity) to
the insulin receptor.
312
α Subunit β Subunit
1 2 3 4 5 6 7 8 910 11121314151617 18
Gene
Tran
s crip
tion
mRNA
mRNA
INR
Figure 2 Type 1 insulin-like growth factor receptor gene and mRNA. Reproduced with
permission from Werner.22
THE IGF-1 GENE
The IGF-1 gene is on the long arm of chromo-
some 12q23–23.15 16 The human IGF-1 gene
consists of six exons, including two leader
exons, and has two promoters.17
IGF binding proteins (IGFBPs)
In the plasma, 99% of IGFs are complexed to
a family of binding proteins, which modulate
the availability of free IGF-1 to the tissues.
There are six binding proteins.18 In humans,
almost 80% of circulating IGF-1 is carried by
IGFBP-3, a ternary complex consisting of one
molecule of IGF-1, one molecule of IGFBP-3,
and one molecule of an 88 kDa protein named
acid labile subunit.19 IGFBP-1 is regulated by
insulin and IGF-120; IGFBP-3 is regulated
mainly by GH but also to some degree by
IGF-1.21
The IGF-1 receptor
The human IGF-1 receptor (type 1 receptor) is
the product of a single copy gene spanning over
100 kb of genomic DNA at the end of the long
arm of chromosome 15q25–26.22 The gene
contains 21 exons (fig 2) and its organisation
resembles that of the structurally related insu-
lin receptor (fig 3).23 The type 1 IGF receptor
gene is expressed by almost all tissues and cell
types during embryogenesis.24 In the liver, the
organ with the highest IGF-1 ligand expres-
sion, IGF-1 receptor mRNA is almost undetec-
table, possibly because of the “downregula-
tion” of the receptor by the local production of
IGF-1. The type 1 IGF receptor is a heterote-
tramer composed of two extracellular spanning
Insulin receptor
Cysteine rich
domains
α Subunits
Tyrosine kinase
domains
β Subunits
Figure 3 Resemblance between the insulin and insulin-like
growth factor 1 (IGF-1) receptors.
www.molpath.com
Laron
á subunits and transmembrane â subunits. The
á subunits have binding sites for IGF-1 and are
linked by disulphide bonds (fig 3). The â subu-
19 20 21
nit has a short extracellular domain, a trans-
membrane domain, and an intracellular do-
main. The intracellular part contains a tyrosine
kinase domain, which constitutes the signal
transduction mechanism. Similar to the insulin
receptor, the IGF-1 receptor undergoes ligand
induced autophosphorylation.25 The activated
IGF-1 receptor is capable of phosphorylating
other tyrosine containing substrates, such as
insulin receptor substrate 1 (IRS-1), and
AUG
continues a cascade of enzyme activations via
phosphatidylinositol-3 kinase (PI3-kinase),
Grb2 (growth factor receptor bound protein
2), Syp (a phophotyrosine phosphatase), Nck
(an oncogenic protein), and Shc (src homology
domain protein), which associated to Grb2,
activates Raf, leading to a cascade of protein
kinases including Raf, mitogen activated pro-
tein (MAP) kinase, 5 G kinase, and others.26
Physiology
IGF-1 is secreted by many tissues and the
secretory site seems to determine its actions.
Most IGF-1 is secreted by the liver and is
transported to other tissues, acting as an endo-
crine hormone.27 IGF-1 is also secreted by
other tissues,28 including cartilagenous cells,
and acts locally as a paracrine hormone (fig
4).29 It is also assumed that IGF-1 can act in an
autocrine manner as an oncogene.30 The role of
IGF-1 in the metabolism of many tissues
including growth has been reviewed re-
cently.31 32
The following is an analysis of whether
IGF-1, the anabolic eVector hormone of pitui-
tary GH, is the “real growth hormone”.
Is IGF-1 “a” or “the” growth hormone?
The discussion on the role of IGF-1 in body
growth will be based on growth in states of
IGF-1 deficiency and the eVects of exogenous
IGF-1 administration. Experiments in nature
(gene deletion or gene mutations) or experi-
mental models in animals, such as gene knock-
outs, help us in this endeavour. In 1966 and
1968,33 34 we described a new type of dwarfism
indistinguishable from genetic isolated GH
deficiency (IGHD), but characterised by high
serum GH values. Subsequent studies revealed
that these patients cannot generate IGF-1.35
IGF-1 receptor This syndrome of GH resistance (insensitiv-
ity) was named by Elders et al as Laron dwarf-
ism,36 a name subsequently changed to Laron
syndrome (LS).37 Molecular studies revealed
that the causes of GH resistance are deletions38
or mutations39 in the GH receptor gene, result-
ing in the failure to generate IGF-1 and a
reduction in the synthesis of several other sub-
stances, including IGFBP-3. This unique
model in humans has enabled the study of the
diVerential eVects of GH and IGF-1.
Growth and development in congenital
(primary) IGF-1 deficiency (LS)
Our group has studied and followed 52
patients (many since birth) throughout child-
hood, puberty, and into adulthood. We found
IGF-1: a growth hormone 313

resulting from underdevelopment of the facial

Growth Prechondrocyte
hormone
bones, small hands, and small feet).33 34 IGF-1
deficiency also causes underdevelopment and
Proximal weakness of the muscular system,43 and impairs
IGF-1 Receptor zone and weakens hair44 and nail growth. These
mRNA findings are identical to those described in
Differentiation IGHD.45 IGF-1 deficiency throughout child-
hood causes dwarfism (final height if un-
treated, 100–135 cm in female and 110–
Early 142 cm in male patients),40 41 with an
IGF-1
chondrocyte abnormally high upper to lower body ratio.41
Intermediate One patient reported from the UK was found
zone
to have a deletion of exons 4 and 5 of the IGF-1
Clonal expansion gene and he too was found to have severe
growth retardation.46
Impaired growth and skeletal development
in the absence of IGF-1 were confirmed in
IGF-1 mice using knockout (KO) of the IGF-1 gene
Maturing
chondrocytes
or GH receptor gene.47–49
Knockout of the IGF-1 gene or the IGF-1
receptor gene reduces the size of mice by
40–45%.49 Lack of the IGF-1 receptor is lethal
Distal at birth in mice owing to respiratory failure
zone caused by impaired development of the dia-
phragm and intercostal muscles.49 In another
model, the mice remained alive and their post-
natal growth was reduced.50
In conclusion, findings in humans and in
animals show that IGF-1 deficiencies causes
pronounced growth retardation in the presence
Figure 4 Paracrine insulin-like growth factor 1 (IGF-1) secretion and endocrine IGF-1 of increased GH values.
targets in the various zones of the epiphyseal cartilage growth zone.
The following is a summary of the results of
that newborns with LS are slightly shorter at the growth stimulating eVects of the adminis-
birth (42–47 cm) than healthy babies (49– tration of exogenous IGF-1 to children and
52 cm), suggesting that IGF-1 has some influ- experimental data.
ence on intrauterine linear growth.40 This fact
is enforced by the findings that already at birth, Growth promoting eVects of IGF-1
and throughout childhood, skeletal maturation The first demonstration that exogenous IGF-1
is retarded, as is organ growth.41 These growth stimulates growth was the administration of
abnormalities include a small brain (as ex- purified hormone to hypophysectomised
pressed by head circumference),41 a small heart rats.51 52 After the biosynthesis of IGF-1 identi-
(cardiomicria),42 and acromicria (small chin, cal to the native hormone,53 trials of its use in

12

10
Growth velocity (cm/year)

0
No. 1 2 3 4 5 6 7 8
sex M M F M M F F M
Patient

CA(y) 3–4 3.3–5.3 4.2–5.2 5.1–7.1 10.1–11.1 11.6–13.6 13.8–16.2 14.6–17.1

BA(y) 2–2.7 1.5–2.6 3.3–4.2 1.8–3.5 6.5–7.9 11.0–13.0 11.0 –13..3 9.0–12.7
Name AJ. Al.B A.N Al.G A.B D.S T.K L.M
Figure 5 Growth velocity before and during insulin-like growth factor 1 (IGF-1) treatment. Note that in infancy, when
the non-growth hormone/IGF-1 dependent growth velocity is relatively high (but low for age), the change induced by
IGF-1 administration is less than in older children.

www.molpath.com
314
Table 1 Linear growth response of children with Laron syndrome treated by means of insulin-like growth factor 1 (IGF-1)
At start
Age range BA Ht SDS
Authors Year Ref. N (years) (years) (m)
Ranke et al 1995 61 31 3.7–19 1.8–13.3 −6.5
Backeljauw et al 1996 62 5 2–11 0.3–6.8 −5.6
Klinger and Laron 1995 63 9 0.5–14 0.2–11 −5.6
Guevarra-Aguirre et al 1997 64 15 3.1–17 4.5–9.3
Guevarra-Aguire et al 64 8 80 b.i.d.
Growth velocity values are mean (SD).
*The younger children had a growth velocity of 5.5 and 6.5 cm/year.
BA, bone age; b.i.d., twice daily; CA, chronological age; i.d., once daily; Ht SDS, height standard deviation score.
humans were begun; first in adults54 and then
in children.55 56 Our group was the first to
introduce long term administration of biosyn-
thetic IGF-1 to children with primary IGF-1
deficiency—primary GH insensitivity or LS.57
The finding that daily IGF-1 administration
raises serum alkaline phosphatose, which is an
indicator of osteoblastic activity, and serum
procollagen,57 58 in addition to IGFBP-3,21 led
to long term treatment. Treatment of patients
with LS was also initiated in other parts of the
world.59–62 The diVerence between us and the
other groups was that we used a once daily
dose, whereas the others administered IGF-1
twice daily.60 Table 1 compares the linear
growth response of children with LS treated by
four diVerent groups. It can be seen that before
treatment the mean growth velocity was
3–4.7 cm/year and that this increased after
IGF-1 treatment to 8.2–9.1 cm/year, followed
by a lower velocity of 5.5–6.4 cm/year in the
next two years. (In GH treatment the highest
growth velocity registered is also in the first
year of treatment.) Figure 5 illustrates the
growth response to IGF-1 in eight children
during the first years of treatment.65 Ranke and
colleagues60 reported that two of their patients
had reached the third centile (Tanner), as did
the patient of Krzisnik and Battelino66; how-
ever, most patients did not reach a normal final
height. The reasons may be late initiation of
treatment, irregular IGF-1 administration,
underdosage, etc. Ranke et al conclude that
long term treatment of patients with LS
promoted growth and, if treatment is started at
an early age, there is a considerable potential
for achieving height normalisation.60 Because
no patient in our group was treated since early
infancy to final height we cannot confirm this
opinion.
When the growth response to GH treatment
in infants with IGHD was compared with that
of IGF-1 in infants with LS we found that the
infants with IGHD responded faster and better
than those with LS.67 However, the small
number of patients and the diVerences in
growth retardation between the two groups
makes it diYcult to reach a conclusion.
Both hormones stimulated linear growth,
but GH seemed more eVective than IGF-1.
One cause may be the greater growth deficit of
the infants with LS than those with IGHD, an
insuYcient dose of IGF-1, or that there is a
www.molpath.com
Laron
Growth velocity (cm/year) Year of treatment
IGF-1 dose
(µg/kg/day) 0 1st 2nd 3rd
(n = 26) (n = 18)
40–120 b.i.d. 3.9 (1.8) 8.5 (2.1) 6.4 (2.2)
(n = 5) (n = 5) (n = 1)
80–120 b.i.d. 4.0 9.3 6.2 6.2
(n = 9) (n = 6) (n = 5)
150–200 i.d 4.7 (1.3) 8.2 (0.8) 6 (1.3) 4.8 (1.3)*
(n = 15) (n = 15) (n = 6)
120 b.i.d. 3.4 (1.4) 8.8 (11) 6.4 (1.1) 5.7 (1.4)
(n = 8) (n = 8)
3.0 (1.8) 9.1 (2.2) 5.6 (2.1)
need for some GH to provide an adequate stem
cell population of prechondrocytes to enable
full expression of the growth promoting action
of IGF-1, as postulated by Green and col-
leagues68 and Ohlson et al.69 All the above find-
ings based on a few clinical studies with small
groups of patients and a few experimental
studies remain at present controversial. The
crucial question is whether there are any, and if
so, whether there are suYcient IGF-1 receptors
in the “progenitor cartilage zone” of the
epiphyseal cartilage (fig 4) to respond to endo-
crine and exogenous IGF-1. Using the man-
dibular condyle of 2 day old ICR mice, Maor et
al showed that these condyles, which resemble
the epiphyseal plates of the long bones, contain
IGF-1 and high aYnity IGF-1 receptors also in
the chondroprogenitor cell layers, which ena-
bles them to respond to IGF-1 in vitro.70
Sims et al,71 using mice with GH receptor
KO showed that IGF-1 administration stimu-
lates the growth (width) of the tibial growth
plate and that IGF-1 has a GH independent
eVect on the growth plate. These findings are
similar to those found when treating hypophy-
sectomised rats with IGF-1.51 52
In conclusion, IGF-1 is an important growth
hormone, mediating the anabolic and linear
growth promoting eVect of pituitary GH
protein. It has a GH independent growth
stimulating eVect, which with respect to
cartilage cells is possibly optimised by the syn-
ergistic action with GH.
1 Tannenbaum GS, Ling N. The interrelationship of growth
hormone (GH)-releasing factor and somatostatin in
generation of the ultradian rhythm of GH secretion. Endo-
crinology 1984;115:1952–7.
2 Laron Z. Growth hormone secretagogues: clinical experi-
ence and therapeutic potential. Drugs 1995;50:595–601.
3 Ghigo E, Boghen M, Casanueva FF, et al., eds. Growth hor-
mone secretagogues. Basic findings and clinical implications.
Amsterdam: Elsevier, 1994.
4 JaVe CA, Ho PJ, Demott-Friberg R, et al. EVects of a
prolonged growth hormone (GH)-releasing peptide infu-
sion on pulsatile GH secretion in normal men. J Clin Endo-
crinol Metab 1993;77:1641–7.
5 Kojima M, Hosada H, Date Y, et al. Ghrelin is a
growth-hormone-releasing acylated peptide from stomach.
Nature 1999;402:656–60.
6 Devesa J, Lima L, Tresquerres AF. Neuroendocrine control
of growth hormone secretion in humans. Trends Endocrinol
Metab 1992;3:175–83.
7 Laron Z. The somatostatin-GHRH-GH-IGF-I axis. In:
Merimee T, Laron Z, eds. Growth hormone, IGF-I and
growth: new views of old concepts. Modern endocrinology and
diabetes, Vol. 4. London-Tel Aviv: Freund Publishing
House Ltd, 1996:5–10.
8 Salmon WD, Jr, Daughaday W. A hormonally controlled
serum factor which stimulates sulfate incorporation by car-
tilage in vitro. J Lab Clin Med 1957;49:825–36.
9 Froesch ER, Burgi H, Ramseier EB, et al. Antibody-
suppressible and nonsuppressible insulin-like activities in
IGF-1: a growth hormone
human serum and their physiologic significance. An insulin
assay with adipose tissue of increased precision and specifi-
city. J Clin Invest 1963;42:1816–34.
10 Daughaday WH, Hall K, Raben MS, et al. Somatomedin: a
proposed designation for the sulfation factor. Nature 1972;
235:107.
11 Rinderknecht E, Humbel RE. Polypeptides with non-
suppressible insulin-like and cell-growth promoting activi-
ties in human serum: isolation, chemical characterization,
and some biological properties of forms I and II. Proc Natl
Acad Sci U S A 1976;73:2365–9.
12 Laron Z. Somatomedin-1 (recombinant insulin-like growth
factor-I). Clinical pharmacology and potential treatment of
endocrine and metabolic disorders. Biodrugs 1999;11:55–
70.
13 Blundell TL, Humbel RE. Hormone families: pancreatic
hormones and homologous growth factors. Nature 1980;
287:781–7.
14 Rinderknecht E, Humbel RE. The amino acid sequence of
human insulin like growth factor I and its structural
homology, with proinsulin. J Biol Chem 1978;253:2769–76.
15 Brissenden JE, Ullrich A, Francke U. Human chromosomal
mapping of genes for insulin-like growth factors I and II
and epidermal growth factor. Nature 1984;310:781–4.
16 Mullis PE, Patel MS, Brickell PM, et al. Growth character-
istics and response to growth hormone therapy in patients
with hypochondroplasia: genetic linkage of the insulin-like
growth factor I gene at chromosome 12q23 to the disease
in a subgroup of these patients. Clin Endocrinol 1991;34:
265–74.
17 Rotwein P. Structure, evolution, expression and regulation
of insulin-like growth factors I and II. Growth Factors 1991;
5:3–18.
18 Hwa V, Oh Y, Rosenfeld RG. The insulin-like growth factor
binding protein (IGFBP) superfamily. Endocr Rev 1999;20:
761–87
19 Lewitt MS, Saunders H, Phuyal JL, et al. Complex
formation by human insulin-like growth factor-binding
protein-3 and human acid-labile subunit in growth
hormone-deficient rats. Endocrinology 1994;134:2402–9.
20 Laron Z, Suikkairi AM, Klinger B, et al. Growth hormone
and insulin-like growth factor regulate insulin-like growth
factor-binding protein-1 in Laron type dwarfism, growth
hormone deficiency and constitutional short stature. Acta
Endocrinol 1992;127:351–8.
21 Kanety H, Karasik A, Klinger B, et al. Long-term treatment
of Laron type dwarfs with insulin-like growth factor I
increases serum insulin-like growth factor-binding protein
3 in the absence of growth hormone activity. Acta Endocri-
nol 1993;128:144–9.
22 Werner H. Molecular biology of the type I IGF receptor. In:
Rosenfeld RG, Roberts CT, Jr, eds. The IGF system—
molecular biology, physiology and clinical applications. Totowa,
NJ: Humana Press, 1999:63–88.
23 Seino S, Seino M, Nishi S, et al. Structure of the human
insulin receptor gene and characterization of its promoter.
Proc Natl Acad Sci U S A 1989;86:114–18.
24 Bondy CA, Werner H, Roberts CT, Jr, et al. Cellular pattern
of insulin-like growth factor I (IGF-I) and type I IGF
receptor gene expression in early organogenesis: compari-
son with IGF-II gene expression. Mol Endocrinol 1990;4:
1386–98.
25 Kato H, Faria TN, Stannard B, et al. Essential role of tyro-
sine residues 1131, 1135, and 1136 of the insulin-like
growth factor-I (IGF-I) receptor in IGF-I action. Mol
Endocrinol 1994;8:40–50.
26 LeRoith D, Werner H, Beitner-Johnson D, et al. Molecular
and cellular aspects of the insulin-like growth factor I
receptor. Endocr Rev 1995;16:143–63.
27 Merimee T, Laron Z, eds. Growth hormone, IGF-I and
growth: new views of old concepts. Modern endocrinology and
diabetes, Vol. 4. London-Tel Aviv: Freund Publishing
House Ltd, 1996.
28 D’Ercole AJ, Applewhite GT, Underwood LE. Evidence
that somatomedin is synthesized by multiple tissues in the
fetus. Dev Biol 1980;75:315–28
29 Nilsson A, Isgaard J, Lindhahl A, et al. Regulation by growth
hormone of number of chondrocytes containing IGF-I in
rat growth plate. Science 1986;233:571–4.
30 Baserga R. The IGF-I receptor in cancer research. Exp Cell
Res 1999;253:1–6.
31 Rosenfeld RG, Roberts CT, Jr, eds. The IGF system—
molecular biology, physiology and clinical applications. Totowa,
NY: Humana Press, 1999.
32 Zapf J, Froesch ER. Insulin-like growth factor I actions on
somatic growth. In: Kostyo J, ed. Handbook of physiology,
Vol. V, Section 7. Philadelphia: American Physiological
Society, 1999:663–99.
33 Laron Z, Pertzelan A, Mannheimer S. Genetic pituitary
dwarfism with high serum concentration of growth
hormone. A new inborn error of metabolism? Isr J Med Sci
1966;2:153–5.
34 Laron Z, Pertzelan A, Karp M. Pituitary dwarfism with high
serum levels of growth hormone. Isr J Med Sci 1968;4:883–
94.
35 Laron Z, Pertzelan A, Karp M, et al. Administration of
growth hormone to patients with familial dwarfism with
high plasma immunoreactive growth hormone. Measure-
ment of sulfation factor, metabolic and linear growth
responses. J Clin Endocrinol Metab 1971;33:332–42.
36 Elders MJ, Garland JT, Daughaday WH, et al. Laron’s
dwarfism: studies on the nature of the defect. J Pediatr
1973;83:253–63.
www.molpath.com
315
37 Laron Z, Parks JS, eds. Lessons from Laron syndrome (LS)
1966–1992. A model of GH and IGF-I action and interac-
tion. Pediatric and Adolescent Endocrinology 1993;24:1–367.
38 Godowski PJ, Leung DW, Meacham LR, et al. Characteriza-
tion of the human growth hormone receptor gene and
demonstration of a partial gene deletion in 2 patients with
Laron type dwarfism. Proc Natl Acad Sci U S A
1989;86:8083–7.
39 Amselem S, Duquesnoy P, Attree O, et al. Laron dwarfism
and mutations of the growth hormone-receptor gene. N
Engl J Med 1989;321:989–95.
40 Laron Z. Laron syndrome—primary growth hormone
resistance. In: Jameson JL, ed. Hormone resistance syn-
dromes. Contemporary endocrinology, Vol. 2. Totowa, NJ:
Humana Press, 1999:17–37.
41 Laron Z. Laron type dwarfism (hereditary somatomedin
deficiency): a review. In: Frick P, Von Harnack GA,
Kochsiek GA, et al, eds. Advances in internal medicine and
pediatrics. Berlin-Heidelberg: Springer-Verlag, 1984:117–
50.
42 Feinberg MS, Scheinowitz M, Laron Z. Echocardiographic
dimensions and function in adults with primary growth
hormone resistance (Laron syndrome). Am J Cardiol 2000;
85:209–13.
43 Brat O, Ziv I, Klinger B, et al. Muscle force and endurance
in untreated and human growth hormone or insulin-like
growth factor-I-treated patients with growth hormone defi-
ciency or Laron syndrome. Horm Res 1997;47:45–8.
44 Lurie R, Ben-Amitai D, Laron Z. Impaired hair growth and
structural defects in patients with Laron syndrome
(primary IGF-I deficiency) [abstract]. Horm Res 2001 [In
press.]
45 Gluckman PD, Gunn AJ, Wray A, et al. Congenital
idiopathic growth hormone deficiency associated with pre-
natal and early postnatal growth failure. J Pediatr
1992;121:920–3.
46 Woods KA, Camacho-Hubner C, Savage MO, et al. Intrau-
terine growth retardation and postnatal growth failure
associated with deletion of the insulin-like growth factor I
gene. N Engl J Med 1996;335:1363–7.
47 Zhou Y, Xu BC, Maheshwari HG, et al. A mammalian
model for Laron syndrome produced by targeted disrup-
tion of the mouse growth hormone receptor/binding
protein gene (the Laron mouse). Proc Natl Acad Sci U S A
1997;94:13215–20.
48 Sjogren K, Bohlooly YM, Olsson B, et al. Disproportional
skeletal growth and markedly decreased bone mineral con-
tent in growth hormone receptor –/– mice. Biochem Biophys
Res Commun 2000;267:603–8.
49 Accili D, Nakae J, Kim JJ, et al. Targeted gene mutations
define the roles of insulin and IGF-I receptors in mouse
embryonic development. J Pediatr Endocrinol Metab 1999;
12:475–85.
50 Holzenberger M, Leneuve P, Hamard G, et al. A targeted
partial invalidation of the insulin-like growth factor-I
receptor gene in mice causes a postnatal growth deficit.
Endocrinology 2000;141:2557–66.
51 Schoenle E, Zapf J, Humbel RE, et al. Insulin-like growth
factor I stimulates growth in hypophysectomized rats.
Nature 1982;296:252–3.
52 Guler H-P, Zapf J, Scheiwiller E, et al. Recombinant human
insulin-like growth factor I stimulates growth and has dis-
tinct eVects on organ size in hypophysectomized rats. Proc
Natl Acad Sci U S A 1988;85:4889–93.
53 Niwa M, Sato Y, Saito Y, et al. Chemical synthesis, cloning
and expression of genes for human somatomedin C (insu-
lin like growth factor I) and 59Val somatomedin C. Ann N
Y Acad Sci 1986;469:31–52.
54 Guler HP, Zapf J, Froesch ER. Short term metabolic eVects
of recombinant human insulin like growth factor in healthy
adults. N Engl J Med 1987;317:137–40.
55 Laron Z, Klinger B, Silbergeld A, et al. Intravenous admin-
istration of recombinant IGF-I lowers serum GHRH and
TSH. Acta Endocrinol 1990;123:378–82.
56 Klinger B, Garty M, Silbergeld A, et al. Elimination charac-
teristics of intravenously administered rIGF-I in Laron
type dwarfs (LTD). Dev Pharmacol Ther 1990;15:196–9.
57 Laron Z, Klinger B, Jensen LT, et al. Biochemical and hor-
monal changes induced by one week of administration of
rIGF-I to patients with Laron type dwarfism. Clin Endocri-
nol 1991;35:145–50.
58 Klinger B, Jensen LT, Silbergeld A, et al. Insulin-like growth
factor-I raises serum procollagen levels in children and
adults with Laron syndrome. Clin Endocrinol 1996;45:423–
9.
59 Underwood LE, Backeljauw P. IGFs: function and clinical
importance of therapy with recombinant human insulin-
like growth factor I in children with insensitivity to growth
hormone and in catabolic conditions. J Intern Med
1993;234:571–7.
60 Ranke MB, Savage MO, Chatelain PG, et al. Long-term
treatment of growth hormone insensitivity syndrome with
IGF-I. Horm Res 1999;51:128–34.
61 Ranke MB, Savage MO, Chatelain PG, et al. Insulin-like
growth factor (IGF-I) improves height in growth hormone
insensitivity: two years results. Horm Res 1995;44:253–64.
62 Backeljauw PF, Underwood LE, The GHIS Collaborative
Group. Prolonged treatment with recombinant insulin-like
growth factor I in children with growth hormone
insensitivity syndrome—a clinical research center study. J
Clin Endocrinol Metab 1996;81:3312–17.
63 Klinger B, Laron Z. Three year IGF-I treatment of children
with Laron syndrome. J Pediatr Endocrinol Metab 1995;8:
149–58.
316 Laron

64 Guevara-Aguirre J, Rosenbloom AL, Vasconez O, et al. Two
year treatment of growth hormone (GH) receptor deficiency
with recombinant insulin-like growth factor-I in 22 children:
comparison of two dosage levels and to GH treated GH defi-
ciency. J Clin Endocrinol Metab 1997;82:629–33.
65 Laron Z, Lilos P, Klinger B. Growth curves for Laron
syndrome. Arch Dis Child 1993;68:768–70.
66 Krzisnik C, Battelino T. Five year treatment with IGF-I of a
patient with Laron syndrome in Slovenia (a follow-up
report). J Pediatr Endocrinol Metab 1997;10:443–7.
67 Laron Z, Klinger B. Comparison of the growth-promoting
eVects of insulin-like growth factor I and growth hormone
in the early years of life. Acta Paediatr 2000;89:38–41.
68 Green H, Morikawa M, Nixon T. A dual eVector theory of
growth hormone action. DiVerentiation 1985;29:195–8.
69 Ohlson C, Bengtsson BA, Isaksson OG, et al. Growth
hormone and bone. Endocr Rev 1998;19:55–79.
70 Maor G, Laron Z, Eshet R, et al. The early postnatal devel-
opment of the murine mandibular condyle is regulated by
endogenous insulin-like growth factor-I. J Endocrinol 1993;
137:21–6.
71 Sims NA, Clement-Lacroix P, Da Ponte F, et al. Bone
homeostatis in growth hormone receptor-null mice is
restored by IGF-I but independent of Stat5. J Clin Invest
2001;106:1095–103.

Reference linking to full text

of more than 200 journals
Toll free links
You can access the FULL TEXT of articles cited in the Journal of Clinical Pathology online if the citation is to one of the
more than 200 journals hosted by HighWire (http://highwire.stanford.edu) without a subscription to that journal.
There are also direct links from references to the Medline abstract for other titles.

www.jclinpath.com

www.molpath.com